Recombinant human thrombopoietin (rhTPO) after autologous bone marrow transplantation : a phase I pharmacokinetic and pharmacodynamic study

• Published in: Bone marrow transplantation (Basingstoke) Vol. 27; no. 3; pp. 261 - 268
• Main Authors: WOLFF, S. N, HERZIG, R, FAY, J, LYNCH, J, ERICSON, S. G, GREER, J. P, STEIN, R, GOODMAN, S, BENYUNES, M. C, ASHBY, M, JONES, D. V
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.02.2001
• Subjects: Adult; Antibodies; Area Under Curve; Autografts; Biological and medical sciences; Bone marrow; Bone marrow transplantation; Bone Marrow Transplantation - adverse effects; Bone Marrow Transplantation - methods; Breast Neoplasms - therapy; Cell differentiation; Cell proliferation; Chemotherapy; Clinical trials; Differentiation; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug toxicity and drugs side effects treatment; Female; Graft Survival - drug effects; Granulocyte colony-stimulating factor; Humans; Immunological tolerance; Injections, Intravenous; Leukocytes (neutrophilic); Medical sciences; Middle Aged; Morbidity; Neutralizing; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; Platelet Count; Platelets; Polyploidy; Progenitor cells; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - standards; Recovery; Stem cell transplantation; Stem cells; Thrombocytopenia; Thrombocytopenia - drug therapy; Thrombocytopenia - etiology; Thrombopoietin; Thrombopoietin - administration & dosage; Thrombopoietin - pharmacokinetics; Thrombopoietin - standards; Toxicity: blood; Transplantation; Transplantation, Autologous - adverse effects; Transplantation, Autologous - methods; Antineoplastic agent; Human; Thrombocytopenia; Toxicity; Cytokine; Hemopathy; Malignant tumor; Biological activity; Thrombopoietin; Mammary gland diseases; Autograft; Chemotherapy; Platelet; Treatment; Phase I trial; Bone marrow; Complication; Graft; Mammary gland; Pharmacokinetics; High dose; Growth factor
• ISSN: 0268-3369; 1476-5365
• DOI: 10.1038/sj.bmt.1702772

Thrombocytopenia following myelotoxic therapy is a common problem and when severe (<20,000/microl) can lead to severe morbidity and mortality. Thrombopoietin (TPO) is a naturally occurring glycosylated peptide which stimulates the differentiation of bone marrow stem cells into megakaryocyte progenitor cells, induces the expression of megakaryocyte differentiation markers, promotes megakaryocyte proliferation, polyploidization and, ultimately, the formation of increased numbers of platelets in the circulation. TPO has now been produced by recombinant technology and has entered clinical trials. This open label phase I study was designed to determine the safety, tolerance and pharmacokinetics of recombinant thrombopoietin (rhTPO) when administered to patients after undergoing high-dose chemotherapy followed by autologous bone marrow transplantation. rhTPO was administered intravenously by bolus injection at doses ranging from 0.3 to 4.8 microg/kg/day every 3 days to 30 patients and 0.6 microg/kg daily to three patients. rhTPO was begun the day after marrow infusion and continued until platelet recovery to >20,000/microl. G-CSF was concomitantly administered to promote myeloid recovery. Serious adverse events or neutralizing antibodies to rhTPO were not observed during the study. Median platelet recovery after ABMT was 19 days (range, 11-41). Neither the dose nor the schedule of rhTPO appeared to have any impact upon the time course of platelet recovery. In this phase I study, rhTPO was found to be well tolerated without the development of neutralizing antibodies and without compromising neutrophil recovery. Platelet recovery was similar for all doses studied warranting further evaluation in phase II and III trials designed to test for platelet recovery efficacy.